Dengue causes significant morbidity and mortality worldwide. Large increases in cases are often associated with a shift in predominant serotypes and/or genotypes. The mechanisms that drive these shifts are not well understood. The proposed work will sequence viruses from the last 25 years from Thailand and characterize the antigenic relationship of these viruses. Humans will mount an immune response to viruses that are antigenically close to one another that will protect individuals from both viruses. For viruses that are antigenically distant, infection with one will not lead to immunity to another. The dengue viruses interact through our immune responses in several distinct ways. Infection with one dengue virus leads to protection from antigenically similar viruses, but can predispose individuals to severe outcome when exposed to other antigenically more distant viruses. The impact of immunity can change over time, initially providing protection, then risk. These interactions can exert selective pressure on circulating dengue viruses. This may be one reason that some lineages are driven to extinction while others persist. Using a new tool to characterize the antigenic relationship of viruses, antigenic cartography, we will characterize changes in dengue viruses over the last 25 years. We will determine whether an individuals antigenic portfolio, or the antigens that an individual has immunity to, is predictive of their risk of dengu disease using samples from a cohort study that has been conducted for >12 years. Finally, we will build models that fit that observed pattern in Thailand well. Relevance to Public Health Understanding how genetic variants of dengue emerge and replace existing variants will help us forecast future incidence, prepare surveillance systems and understand drivers of individual risk. Multiple candidate dengue vaccines are currently in development. Understanding the impact of these vaccines, should they become licensed and used widely, on circulating dengue viruses is critical to their optimal use, continued efficacy and population safety.